tbuckley/cabot-search huggingface dataset:
Periodontitis may induce gut microbiota dysbiosis via salivary microbiota
Authors: Jun Bao, Lili Li, Yangheng Zhang, Min Wang, Faming Chen, Shaohua Ge, Bin Chen, Fuhua Yan
Journal: International Journal of Oral Science (2022)

Abstract The aim of this study was to identify whether periodontitis induces gut microbiota dysbiosis via invasion by salivary microbes. First, faecal and salivary samples were collected from periodontally healthy participants (PH group, n = 16) and patients with severe periodontitis (SP group, n = 21) and analysed by 16S ribosomal RNA sequencing. Significant differences were observed in both the faecal and salivary microbiota between the PH and SP groups. Notably, more saliva-sourced microbes were observed in the faecal samples of the SP group. Then, the remaining salivary microbes were transplanted into C57BL6/J mice (the C-PH group and the C-SP group), and it was found that the composition of the gut microbiota of the C-SP group was significantly different from that of the C-PH group, with Porphyromonadaceae and Fusobacterium being significantly enriched in the C-SP group. In the colon, the C-SP group showed significantly reduced crypt depth and zonula occludens-1 expression. The mRNA expression levels of pro-inflammatory cytokines, chemokines and tight junction proteins were significantly higher in the C-SP group. To further investigate whether salivary bacteria could persist in the intestine, the salivary microbiota was stained with carboxyfluorescein diacetate succinimidyl ester and transplanted into mice. We found that salivary microbes from both the PH group and the SP group could persist in the gut for at least 24 h. Thus, our data demonstrate that periodontitis may induce gut microbiota dysbiosis through the influx of salivary microbes.
S298: CS585 IS A FIRST-IN-CLASS COMPOUND TARGETING THE IP RECEPTOR FOR PREVENTION OF THROMBOSIS WITHOUT INCREASED RISK OF BLEEDING
Authors: S. Lambert, R. Adili, P. Yalavarthi, N. Rhoads, B. Dahlof, A. White, N. Bergh, M. Holinstat
Journal: HemaSphere (2022)

Background: Uncontrolled platelet activation leads to the formation of occlusive thrombi resulting in myocardial infarction, stroke, VTE and critical limb ischemia. There is an unmet need for more efficacious anti-thrombotics with less bleeding in this area. Our group recently identify a novel oxidized lipid in the blood that potently and selectively inhibits platelet activation through activation of the prostacyclin receptor. Aims: Develop a first-in-class antiplatelet drug, CS585, that potently and selectively inhibits platelet reactivity and thrombosis without altering hemostasis and bleeding risk. Methods: We developed a mimetic of the oxidized lipid shown to selectively bind to and activate the prostacyclin receptor. Using human platelets, we assessed the ability of CS585 to inhibit platelet activation by assessing 1)aggregometry, 2)adhesion under arterial flow, and 3) granule secretion and integrin activation using flow cytometry. We additionally assessed thrombosis in vivo in 2 different mouse models as well as bleeding. Finally, we assessed potential off-target effects using thromboelastography (TEG). Results: CS585 potently inhibited both collagen and thrombin-induced platelet aggregation. This inhibition was confirmed by measuring inhibition of αIIbβ3 activation, α-granule secretion, and dense-granule secretion by flow cytometry. Selectivity was confirmed in human platelets by demonstrating a full reversal of inhibition when the IP receptor was pharmacologically blocked or genetically eliminated in IP receptor knockout mice. In vivo inhibition of injury-induced thrombosis in the small (laser-induced cremaster thrombosis model) and large (FeCl3-induced carotid artery thrombosis model) vessels by CS585 was demonstrated and no increased risk for bleeding was observed using the tail vein bleeding model. Finally, TEG experiments in human blood spiked with CS585 demonstrated no delay or decrease in clot strength confirming the tail vein bleeding assay experiments in the mouse. Summary/Conclusion: We have shown for the first time that CS585, a first-in-class analog of an oxidized lipid in the blood potently and selectively activates the prostacyclin receptor resulting in inhibition of human and mouse platelet activation and thrombosis without an increased risk of bleeding. This discovery represents a new class of inhibitors for prevention of platelet activation and thrombosis and protection from myocardial infarction, stroke, VTE, and critical limb ischemia.
P685: REAL WORLD EVIDENCE OF IMPACT OF ATRIAL FIBRILLATION ON CLINICAL AND ECONOMIC OUTCOMES IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: K. Yang, T. Liu, B. Tang, A. Chanan-Khan
Journal: HemaSphere (2022)

Background: While the incidence of atrial fibrillation (AF) in chronic lymphocytic leukemia (CLL) has been increasing, the implications of AF in real-world CLL patients remain understudied. Aims: This study aimed to assess the impact of AF on clinical and economic outcomes in CLL patients. Methods: This retrospective observational study used the US IBM MarketScan® commercial claims/Medicare supplement database (2017-2020) to identify newly diagnosed CLL patients (≥18 years) and incidence of AF after index date, defined as the first CLL diagnosis date. Patients were followed for ≥3-months pre-index, and from index to last follow-up or death. In addition to patient characteristics, clinical outcomes (incidence of heart failure [HF], bleeding and stroke) and economic outcomes (costs and healthcare resource utilization [HRU]) were compared between CLL patients with AF (CLL+AF) and CLL patients without AF (CLL-AF). HRU was evaluated by inpatient, outpatient, ER, and pharmacy visits. Multivariable regression analyses were conducted to examine the association between AF and clinical outcomes. Results: Among a total of 16,800 newly diagnosed CLL patients included in the study, 20% developed AF. CLL+AF were significantly older than CLL-AF (median: 77 vs 62 years; P < .001). Compared to CLL-AF, CLL+AF also had significantly more comorbidities at baseline, as shown by higher Charlson comorbidity index (CCI) (median: 1.0 vs 3.0; P < .001) and more patients with previous AF history (0.3% vs 8.4%; P < .001). Further assessing clinical outcomes in CLL+AF vs CLL-AF, significantly higher incidence of HF (26.3% vs 3.0%; P < .001), bleeding (12.2% vs 4.8%; P < .001) and stroke (6.6% vs 1.2%; P < .001) were observed. For HRU, CLL+AF were reported to have significantly higher rates of ER visits (29.4% vs 12.9%; P < .001) and hospitalizations (42.2% vs 14.5%; P < .001) than CLL-AF. In CLL+AF, the average total AF-related costs were $13,520.21 within 30 days after AF diagnosis, and $22,304.82 within 60 days after AF diagnosis. Controlling for demographics and comorbidities, multivariable regressions reported statistically significant associations between AF and HF, as well as AF and stroke (Table). Image:Summary/Conclusion: This real-world study reported significantly higher incidence of HF, bleeding and stroke incurred by CLL patients who developed AF compared with those who did not. The presence of HF, bleeding and stroke further increased HRU and costs. These findings highlight the importance of better disease management and treatment selection to prevent AF in CLL patients.
Prevalence of Poor Mental Health Among Adolescents in Kabul, Afghanistan, as of November 2021
Authors: Sayed Jafar Ahmadi, Laura Jobson, Arul Earnest, Daniel McAvoy, Zeinab Musavi, Nasratullah Samim, Sayed Ali Akbar Sarwary
Journal: JAMA Network Open (2022)

This study has some limitations.Owing to heightened security, we were unable to adopt a random-sampling design, we could only recruit from Kabul, it was difficult to recruit girls, the sample size was limited, and the cross-sectional design precluded any inference of causation.Follow-up studies are needed to monitor the chronicity of psychiatric disorders among adolescents in Afghanistan.Adolescents in Afghanistan, especially girls, are experiencing significant mental health problems.However, Afghanistan's health system is struggling, and foreign humanitarian aid has diminished substantially. 1 There is a need for mental health interventions that are tailored to the current political and social environment in Afghanistan.Furthermore, clinicians treating recently arrived adolescent refugees from Afghanistan must consider the emotional and behavioral presentations within the context of the political, historical, and social experiences of this population.
P817: SYNDROMES PREDISPOSING TO LEUKEMIA ARE A MAJOR CAUSE OF INHERITED CYTOPENIAS IN CHILDREN
Authors: O. Gilad, O. Dgany, S. Noy -Lotan, T. Krasnov, J. Yacobovich, R. Rabinowicz, T. Goldberg, A. Kuperman, A. Abu-Quider, H. Miskin, N. Kapelushnik, N. Mandel-Shorer, S. Shimony, D. Harlev, T. Ben-Ami, E. Adam, C. Levin, S. Aviner, R. Elhasid, S. Berger-Achituv, L. Chaitman-Yerushalmi, Y. Kodman, N. Oniashvilli, M. Hameiri- Grosman, S. Izraeli, H. Tamary, O. Steinberg-Shemer
Journal: HemaSphere (2022)

Background: Prolonged cytopenias are a non-specific sign with a wide differential diagnosis. Among inherited disorders, cytopenias predisposing to leukemia require a timely and accurate diagnosis to ensure appropriate medical management, including adequate monitoring and stem-cell transplantation prior to the development of leukemia. Aims: We aimed to define the types and prevalences of the genetic causes leading to persistent cytopenias in children. Methods: The study comprises children with persistent cytopenias, myelodysplastic syndrome (MDS), aplastic anemia, or suspected inherited bone marrow failure syndromes, who were referred for genetic evaluation from all pediatric hematology centers in Israel during 2016-2019. For variant detection, we used a custom-made targeted next-generation sequencing panel covering 226 genes known to be mutated in inherited cytopenias followed, if needed, by whole exome sequencing. Sanger sequencing was used for validation. Results: In total, 189 children with persistent cytopenias underwent a genetic evaluation. Pathogenic and likely pathogenic variants were identified in 59 patients (31.2%), including 47 with leukemia predisposing syndromes. Most of the latter (32, 68.1%) had inherited bone marrow failure syndromes, 9 (19.1%) had inherited thrombocytopenia predisposing to leukemia, and 3 (6.4%) had congenital neutropenia. Twelve patients had cytopenias with no known leukemia predisposition, including nine children with inherited thrombocytopenia and three with congenital neutropenia (not yet known to predispose to leukemia). Importantly only 3 had myelodysplastic syndrome. Thus, the majority of leukemia predisposition could not have been deduced from the morphological presence of MDS Summary/Conclusion: almost one-third of 189 children referred with persistent cytopenias had an underlying inherited disorder; 79.7% of whom had a germline predisposition to leukemia. Precise diagnosis of children with cytopenias should direct follow-up and management programs and may positively impact disease outcome.
The transcription factor RFX5 coordinates antigen-presenting function and resistance to nutrient stress in synovial macrophages
Authors: Zhaolan Hu, Tuantuan V. Zhao, Tao Huang, Shozo Ohtsuki, Ke Jin, Isabel N. Goronzy, Bowen Wu, Matthew P. Abdel, Jacob W. Bettencourt, Gerald J. Berry, Jörg J. Goronzy, Cornelia M. Weyand
Journal: Nature Metabolism (2022)
S176: DARATUMUMAB CARFILZOMIB LENALIDOMIDE AND DEXAMETHASONE AS INDUCTION THERAPY IN HIGH-RISK TRANSPLANT ELIGIBLE NEWLY DIAGNOSED MYELOMA PATIENTS: RESULTS OF THE PHASE 2 STUDY IFM 2018-04
Authors: C. Touzeau, A. Perrrot, C. Hulin, S. Manier, M. Macro, M.-L. Chretien, L. Karlin, O. Decaux, C. Jacquet, M. Tiab, X. Leleu, L. Planchce, H. Avet-Loiseau, P. Moreau
Journal: HemaSphere (2022)

Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed myeloma multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with favorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improved response rate and progression free-survival in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improved outcome of HR TE NDMM patients (EMN02, STAMINA). Aims: The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) is evaluating an intensive strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577). Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Stategy includes Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara-KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance. The primary endpoint was the feasibility of this intensive strategy. Here, we report efficacy and safety analysis of Dara-KRD induction. Results: Fifty patients with previously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers Median age was 57 (range 38 -65). ISS stage 3 was present in 12 (24%) patients. Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n=20, 40%), t(4;14) (n=26, 52%) or t(14;16) (n=10,20%). Forty-six patients completed Dara-KRD induction. Two patients discontinued treatment due to severe adverse event (COVID-19 infection, n=1; drug-induced hepatitis, n=1) and 2 patients discontinued treatment due to disease progression. Grade 3-4 treatment related adverse event (>5% of patients) were neutropenia (38%), anemia (14%), thrombocytopenia (8%), infection (6%), renal insufficiency (6%) and deep-vein thrombosis (6%). Two patients (6%) experienced stem-cell collection failure. Overall response rate was 96%, including 92 % ≥ very good partial response. Among 37/46 evaluable patients post induction, Minimal Residual Disease negativity rate (NGS, 10-5) was 62%. Summary/Conclusion: Dara-KRD as induction prior ASCT is safe and allows deep responses in TE NDMM patients with high-risk cytogenetic profile. IFM 2018-04 study is ongoing and longer follow-up is needed to evaluate safety and efficacy of the overall strategy with Dara-KRD induction and consolidation plus double transplant in this subset of HR patients.
P1437: NOVEL ERYTHROID ENHANCERS IMPROVE GENE THERAPY VECTORS FOR BETA-HEMOGLOBINOPATHIES
Authors: N. Psatha, P. Sova, G. Georgolopoulos, M. Iwata, K. Paschoudi, A. Kirtsou, T. Ulyanova, J. A. Stamatoyannopoulos, E. Yannaki, T. Papayannopoulou, J. Vierstra
Journal: HemaSphere (2022)

Background: Regulation of gene expression during cell development and differentiation is chiefly orchestrated by distal noncoding regulatory elements. Massively parallel reporter gene assays (MPRAs) have provided tremendous insights into transcriptional enhancers’ function and principles of regulation. Aims: Understanding the enhancer’s mode of function serves an important role for contemporary medicine as they constitute a prominent feature of therapeutic vectors. In the present study we developed a screening assay using a clinically relevant viral vector while simultaneously maintaining genomic context and cell type relevance. Methods: We designed a library of 15,000 short sequences (200bp) derived from a set of developmentally active DHS elements during human ex vivo erythropoiesis and cloned them into a GFP reporter lenti-viral vector. These elements proved to not only be highly cell type restricted but also stage specific. Subsequently, two of these newly identified, compact, strong erythroid enhancers were cloned in a BCL11A-shRNA vector similar to what is currently used in clinical trials for beta-hemoglobinopathies to replace the widely applied, yet of considerable size, β-globin μLCR. Results: The novel gene therapy vectors yielded 2-5 times higher viral titers during production due to their small size, while they proved to be more efficient in transducing normal CD34+ cells at the same multiplicity of infection. Their ability to reactivate the endogenous gamma globin expression within the transduced population was equivalent to that of the μLCR-BCL11a-shRNA vector. Engraftment and multilineage reconstitution of the transduced cells after xenotransplantation in a mouse model was similar in all groups, with the new vectors yielding higher transduction and HbF levels over time. Finally, transduction of CD34+ cells from patients with beta-thalassemia major with the new vectors resulted in higher HbF expression coupled with phenotypic correction of their ex vivo generated erythroid cells. Summary/Conclusion: Collectively, our data provide further insights into enhancer biology in erythropoiesis with wider implications into the development of a new generation of highly cell type-specific and efficacious viral vectors for human gene therapy.
P1241: THE INCIDENCE AND SURVIVAL OUTCOMES OF PATIENTS WITH PRIMARY GASTRIC T-CELL LYMPHOMA: A SEER POPULATION-BASED STUDY
Authors: M. Zhang, F. Xiao, J. Hou, H. Huang
Journal: HemaSphere (2022)

Background: Primary gastric T-cell lymphoma (PG-TCL) is a rare neoplasm with a handful of sporadic case reports or small retrospective series study in the literature. Due to its extreme rarity, the clinicopathological entity and survival of PG-TCL have not been well characterized. Aims: We aimed to investigate the epidemiology, clinical features and prognosis of PG-TCL. Methods: A total of 164 patients diagnosed with PG-TCL from 1975 to 2016 extracted from the Surveillance, Epidemiology, and End Results Program (SEER) database were analyzed. Overall survival (OS) and cancer-specific survival (CSS) curves were explored using the Kaplan-Meier method. Cox proportional hazard regression was applied to investigate the independent prognostic factors of OS and CSS. Nomograms were established to predict survival possibilities. Results: The age-adjusted incidence rate of PG-TCL was 0.0091 per 100,000 person-years and increased with age. The median age at diagnosis was 65 years old with male predominance. The major histological type was peripheral T-cell lymphoma, NOS (63.4%). The 1-, 2-, and 5-year OS were 45.5%, 34.7%, and 23.5%, respectively while the 1-, 2-, and 5-year CSS were 47.4%, 37.3%, and 29.6%%, respectively. Multivariate Cox regression analysis revealed that age at diagnosis, chemotherapy and radiotherapy were the independent prognostic factors for OS. Chemotherapy combined with radiotherapy could significantly improve patients’ OS compared with chemotherapy alone. Moreover, age at diagnosis was also the independent prognostic factor for CSS. Nomograms for PG-TCL were developed to predict 1-, 2-, and 5-year OS possibility (Figure A). The accuracy of nomograms was verified by high concordance index and good agreement with the predicted value in calibration plots. Image:Summary/Conclusion: PG-TCL is a rare neoplasm with low incidence. Patients with PG-TCL generally exhibited poor prognosis. Use of Chemotherapy plus radiotherapy was associated with favorable OS.
Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease
Authors: Gabriella Assante, Sriram Chandrasekaran, Stanley Ng, Aikaterini Tourna, Carolina H. Chung, Kowsar A. Isse, Jasmine L. Banks, Ugo Soffientini, Celine Filippi, Anil Dhawan, Mo Liu, Steven G. Rozen, Matthew Hoare, Peter Campbell, J. William O. Ballard, Nigel Turner, Margaret J. Morris, Shilpa Chokshi, Neil A. Youngson
Journal: Genome Medicine (2022)

Abstract Background The incidence of non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is increasing worldwide, but the steps in precancerous hepatocytes which lead to HCC driver mutations are not well understood. Here we provide evidence that metabolically driven histone hyperacetylation in steatotic hepatocytes can increase DNA damage to initiate carcinogenesis. Methods Global epigenetic state was assessed in liver samples from high-fat diet or high-fructose diet rodent models, as well as in cultured immortalized human hepatocytes (IHH cells). The mechanisms linking steatosis, histone acetylation and DNA damage were investigated by computational metabolic modelling as well as through manipulation of IHH cells with metabolic and epigenetic inhibitors. Chromatin immunoprecipitation and next-generation sequencing (ChIP-seq) and transcriptome (RNA-seq) analyses were performed on IHH cells. Mutation locations and patterns were compared between the IHH cell model and genome sequence data from preneoplastic fatty liver samples from patients with alcohol-related liver disease and NAFLD. Results Genome-wide histone acetylation was increased in steatotic livers of rodents fed high-fructose or high-fat diet. In vitro, steatosis relaxed chromatin and increased DNA damage marker γH2AX, which was reversed by inhibiting acetyl-CoA production. Steatosis-associated acetylation and γH2AX were enriched at gene clusters in telomere-proximal regions which contained HCC tumour suppressors in hepatocytes and human fatty livers. Regions of metabolically driven epigenetic change also had increased levels of DNA mutation in non-cancerous tissue from NAFLD and alcohol-related liver disease patients. Finally, genome-scale network modelling indicated that redox balance could be a key contributor to this mechanism. Conclusions Abnormal histone hyperacetylation facilitates DNA damage in steatotic hepatocytes and is a potential initiating event in hepatocellular carcinogenesis.